The opening of a DNA base pair is a simple reaction that is a prerequisite for replication, transcription, and other vital biological functions. Understanding the mo lecular mechanisms of biological reactions is crucial for predicting and, ultimately, controlling them. Realistic computer simulations of the reactions can provide the needed understanding. To model even the simplest re action in aqueous solution requires hundreds of hours of supercomputing time. We have used molecular dy namics techniques to simulate fraying of the ends of a six base pair double strand of DNA, [TCGCGA]2, where the four bases of DNA are denoted by T (thymine), C (cytosine), G (guanine), and A (adenine), and to estimate the free energy barrier to this process. The calculations, in which the DNA was surrounded by 2,594 water mol ecules, required 50 hours of CRAY-2 CPU time for every simulated 100 picoseconds. A free energy barrier to fraying, which is mainly characterized by the movement of adenine away from thymine into aqueous environ ment, was estimated to be 4 kcal/mol. Another fraying pathway, which leads to stacking between terminal adenine and thymine, was also observed. These detailed pictures of the motions and energetics of DNA base pair opening in water are a first step toward understanding how DNA will interact with any molecule.
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References
1.
Buckner, J.K., and Jorgensen, W.1989. Energetics and hydration of the constituent ion pairs of tetramethylammonium chloride. J. Am. Chem. Soc.111:2507-2516.
2.
Dang, L.X., and Kollman, P.A.1990. Molecular dynamics simulations study of the free energy association of 9-CH3 adenine and I-CH3 thymine bases in water. J. Am. Chem. Soc.112:503-507.
3.
Dang, L.X., and Pettitt, B.M.1987. Chloride ion pairs in water. J. Am. Chem. Soc.109:5531-5532.
4.
Greengard, L.1988. The rapid evaluation of potential fields in particle systems . Cambridge: MIT Press.
5.
van Gunsteren, W.F., Berendsen, H.J.C., Geurtsen, R.G., and Zwinderman, H.R.J.1986. A molecular dynamics computer simulation of an eight-base-pair DNA fragment in aqueous solution. Comparison with experimental two-dimensional NMR data. Ann. N.Y. Acad. Sci.482:287-303.
6.
Huston, S.E. and Rossky, P.J.1989. Free energies of association for the sodium-dimethyl phosphate ion pair in aqueous solution. J. Phys. Chem.93:7888-7895.
7.
Jorgensen, W.L., Chandresekhar, J., Madura, J., Impey, R.W., and Klein, M.L.1983. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys.79:926-935.
8.
Jorgensen, W.L., Madura, J.D., and Swenson, C.J.1984. Optimized intermolecular potential functions for liquid hydrocarbons. J. Am. Chem. Soc.106:6638-6646.
9.
Katz, L., and Penman, S.1966. Association by hydrogen bonding of free nucleosides in non-aqueous solution. J. Mol. Biol.15:220-231.
10.
Katznelson, J.1989. Computational structure of the N-body problem. SIAM J. Sci. Comput.10:787-815.
11.
Keepers, J., Kollman, P.A., and James, T.L.1984. Molecular mechanical studies of base-pair opening in d(CGCGC):d(GCGCG), dG5dC5, d(TATAT): d(ATATA), and dA5dT 5 in the B and Z forms of DNA. Biopolymers23:2499-2511.
12.
Kyogoku, Y., Lord, R.C., and Rich, A.1967. An infrared study of hydrogen bonding between adenine and uracil derivatives in chloroform solution. J. Am. Chem. Soc.89:496-503.
13.
Laaksonen, A., Nilsson, L., Jönssson, B., and Teleman, O.1989. Molecular dynamics simulation of double helix Z-DNA in solution. Chem. Phys.129:175-183.
14.
Marky, L.A., Frank, R., Blocker, H., and Breslauer, K.J.1986. Predicting DNA duplex stability from the base sequence . Proc. Natl. Acad. Sci. USA83:3746.
15.
Owenson, B., and Pohorille, A.1987. COSMOS—software package for computer simulations of molecular systems developed atNASA- Ames Research Center.
16.
Pardi, A., Morden, K.M., Patel, D.J., and Tinoco, I. Jr.1982. Kinetics for exchange of the imino protons in the d(C-G-C-G-A-A-T-T-C-G-C-G) double helix and in two similar helices that contain a G:T base pair d(C-GT-GA-AT-T-C-G-C-G) and an extra adenine d(C-GC-A-G-A-A-T-T-C-G-C-G). Biochemistry21:6567-6574.
17.
Pitha, J., Jones, N., and Pithova, P.1966. The specificity of hydrogen bond formation between derivatives of nucleic acid bases and some analogs. Can. J. Chem.44:1045-1050.
18.
Pettitt, B.M., and Rossky, P.J.1986. Alkali halides in water: ion-solvent correlations and ion-ion potentials of mean force at infinite dilution. J. Chem. Phys.84:5836-5844.
19.
Pohorille, A., Burt, S.K., and MacElroy, R.D.1984. Monte Carlo simulation of the influence of solvent on nucleic acid base associations. J. Am. Chem. Soc.106:402-409.
20.
Pohorille, A., and Pratt, L.R.1986. Theoretical methods for obtaining free energies of biomolecular equilibria in aqueous solutions. Methods Enzymol.127:64-78.
21.
Pohorille, A., Pratt, L.R., Burt, S.K., and MacElroy, R.D.1984. Solution influence on biomolecular equilibria: nucleic acid base associations. J. Biomol. Struct. Dynam.1:1257-1279.
22.
Pratt, L.R.1986. A statistical method for identifying transition states in high dimensional problems. J. Chem. Phys.85:5045-5048.
23.
Saenger, W.1984. Principles of nucleic acid structure. New York: Springer-Verlag.
24.
Schweizer, M.P., Broom, A.D., Ts'o, P.O.P., and Hollis, D.P.1968. Studies of inter- and intramolecular interaction in mono-nucleotides by proton magnetic resonance. J. Am. Chem. Soc.90:1042-1055.
25.
Seibel, G.L., Singh, U.C., and Kollman, P.A.1985. A molecular dynamics simulation of double-helical B-DNA including counterions and water. Proc. Natl. Acad. Sci. USA82:6537-6540.
26.
Singh, U.C., Weiner, P.K., Caldwell, J.W., and Kollman, P.A.1986. AMBER(UCSF) version 3.0, Department of Pharmaceutical Chemistry, University of California, San Francisco.
27.
Tidor, B., Irikura, K.K., Brooks, B.R., and Karplus, M.1983. Dynamics of DNA oligomers. J. Biomol. Struct. Dynam.1:231-252.
28.
Ts'o, P. O. P., Melvin, I. S., and Olson, A. C. 1963. Interactions and associations of bases and nucleosides in aqueous solution. J. Am. Chem. Soc.85:1289-1296.
29.
Verlet, L.1967. Computer "experiments" on classical fluids. I. Thermodynamical properties of Lennard-Jones molecules. Phys. Rev.159:98-103.
30.
Weiner, S.J., Kollman, P.A., Singh, U.C., Ghio, C., Alagno, G., Profeta, S., and Weiner, P.K.1984. A new force field for molecular mechanical simulation of nucleic acids and proteins. J. Am. Chem. Soc.106:765-784.
31.
Weiner, S.J., Kollman, P.A., Nguyen, D.T., and Case, D.A.1986. An all atom force field for simulations of proteins and nucleic acids. J. Comp. Chem.7:230-252.
32.
Westhof, E., Chevier, B., Gallion, S.L., Weiner, P.K., and Levy, R.M.1986. Temperature-dependent molecular dynamics and restrained X-ray refinement simulations of a Z-DNA hexamer. J. Mol. Biol.190:699-712.
33.
Yanson, I.K., Teplitsky, A.B., and Sukhodub, F.L.1979. Experimental studies of molecular interactions between nitrogen bases of nucleic acids. Biopolymers18:1149-1170.
34.
Yip, V., and Elber, R.1989. Calculations of a list of neighbors in molecular dynamics simulations. J. Comp. Chem.10:921-927.
